ABSTRACT Effective prevention of substance misuse and related harms, such as HIV risk behaviors and sexually transmitted infection (STI), for females depends critically on identifying mechanisms underlying these adverse health outcomes. To address this gap, the Pittsburgh Girls Study (PGS) renewal aims to identify female- specific personal and social environmental mechanisms of risk and resilience underlying the course of substance use and substance use disorder (SUD), HIV risk behaviors, and STI through age 25, given that these outcomes peak through this age. PGS is a large longitudinal community-based study of females (N=2,451; 52% Black, 41% White), with assessments starting in childhood (ages 5-8), that is uniquely positioned to identify mechanisms of risk and resilience underlying the course of SUD and health outcomes (e.g., STI), and how these mechanisms may differ for Black and White females. The proposed renewal will support annual assessments of substance use/SUD, physical (e.g., STI) and mental health conditions, and personal (e.g., cognition) and environmental (e.g., neighborhood conditions) mechanisms of risk and resilience, through age 25 in all four PGS age cohorts. The renewal aims to: (1) identify processes that explain higher rates of certain types of substance use (e.g., cigarettes), among White, compared to Black, females; (2) determine mechanisms by which substance use is associated with HIV risk behaviors, STI, and unintended pregnancy; and (3) test mechanisms through which substance use affects and is affected by young adult developmental transitions (e.g., parenthood). The project also will explore how cognitive functioning, substance use, and HIV risk behaviors are linked over time in young adulthood. The design of PGS is innovative in its focus on females, who are understudied relative to males; a sampling strategy that permits examination of racial differences in mechanisms of risk and resilience underlying SUD, and racial disparities in health outcomes among Black and White females; and use of cutting-edge statistical methods to reveal interactions between individual, environmental, and developmental factors that influence SUD course and young adult outcomes. Results have implications for developing multi-level strength-based interventions targeting personal and environmental risk and resilience mechanisms at specific points in time, given that intervention at one level, or at a single time point, will have limited impact. PGS renewal activities will generate a female-specific developmental model of personal and environmental mechanisms of risk and resilience underlying substance use and health outcomes, which may differ for Black and White females. This innovative model will be used to specify ?what? intervention content, delivered at which level (individual, community), should be given ?when? and ?to whom? to effectively prevent substance misuse and promote healthy development in young women.